Abstract
Intracellular chloride (Cl–) levels in mature neurons must be tightly regulated for the maintenance of fast synaptic inhibition. In the mature central nervous system (CNS), synaptic inhibition is primarily mediated by gamma-amino butyric acid (GABA), which binds to Cl– permeable GABAA receptors (GABAARs). The intracellular Cl– concentration is primarily maintained by the antagonistic actions of two cation-chloride cotransporters (CCCs): Cl–-importing Na+-K+-Cl– co-transporter-1 (NKCC1) and Cl– -exporting K+-Cl– co-transporter-2 (KCC2). In mature neurons in the healthy brain, KCC2 expression is higher than NKCC1, leading to lower levels of intracellular Cl–, and Cl– influx upon GABAAR activation. However, in neurons of the immature brain or in neurological disorders such as epilepsy and traumatic brain injury, impaired KCC2 function and/or enhanced NKCC1 expression lead to intracellular Cl– accumulation and GABA-mediated excitation. In Huntington’s disease (HD), KCC2- and NKCC1-mediated Cl–-regulation are also altered, which leads to GABA-mediated excitation and contributes to the development of cognitive and motor impairments. This review summarizes the role of Cl– (dys)regulation in the healthy and HD brain, with a focus on the basal ganglia (BG) circuitry and CCCs as potential therapeutic targets in the treatment of HD.
Highlights
Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by involuntary choreatic movements, cognitive disturbances, and mood disorders (Ghosh and Tabrizi, 2018)
HD is caused by a triple cytosine-adenine-guanine (CAG) repeat expansion in the gene encoding for the ubiquitously expressed Huntingtin (Htt) protein (The Huntington’s Disease Collaborative Research Group, 1993), with the CAG repeat length corresponding to the age of onset and disease severity (Snell et al, 1993)
This review focuses on cation-chloride cotransporters (CCCs) dysfunction in mature neurons, the neurodevelopmental defects in HD and the importance of gamma-amino butyric acid (GABA) signaling during the development of neural networks (Ben-Ari, 2002) presents the possibility that in HD, specific neurons may have failed to undergo the necessary “developmental switch” in GABA polarity, which we describe below
Summary
Intracellular chloride (Cl−) levels in mature neurons must be tightly regulated for the maintenance of fast synaptic inhibition. In the mature central nervous system (CNS), synaptic inhibition is primarily mediated by gamma-amino butyric acid (GABA), which binds to Cl− permeable GABAA receptors (GABAARs). In mature neurons in the healthy brain, KCC2 expression is higher than NKCC1, leading to lower levels of intracellular Cl−, and Cl− influx upon GABAAR activation. In neurons of the immature brain or in neurological disorders such as epilepsy and traumatic brain injury, impaired KCC2 function and/or enhanced NKCC1 expression lead to intracellular Cl− accumulation and GABA-mediated excitation. In Huntington’s disease (HD), KCC2- and NKCC1mediated Cl−-regulation are altered, which leads to GABA-mediated excitation and contributes to the development of cognitive and motor impairments.
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